Intracytoplasmic accumulation of keratan sulfate is a hallmark of granular cell tumor.

Granular cell tumor (GCT) is a relatively rare neoplasm characterized by abundant eosinophilic intracytoplasmic granules. More than three decades ago, Ehara and Katsuyama reported that GCT granules are recognized by the anti-keratan sulfate (KS) monoclonal antibody 5D4 and suggested that 5D4 could serve as a diagnostic marker for GCT. However, due to the small number of samples analyzed and incomplete structural analysis of KS, use of 5D4 as a GCT marker has not yet been widely accepted. To confirm its use as a GCT marker, we performed quantitative immunohistochemical analysis of GCT (n = 27) and other GCT-mimicking tumors/lesions (n = 82) including schwannoma (n = 10), neurofibroma (n = 10), melanocytic nevus (n = 10), leiomyoma (n = 10), gastrointestinal stromal tumor (GIST) (n = 10), malignant melanoma (n = 10), dermatofibroma (n = 10), angiosarcoma (n = 10) and malakoplakia (n = 2) using 5D4 and two other anti-KS monoclonal antibodies, R-10G and 297-11A, in combination with two endoglycosidases, keratanase II and endo-β-galactosidase. We found that most GCT tissues were immunostained with 5D4 and 297-11A, although tumors/lesions mimicking GCT showed minimal staining. Moreover, structural analysis revealed that KS accumulated in GCT consisted of both highly sulfated and low-sulfated KS located at non-reducing and reducing termini, respectively. Here we propose that intracytoplasmic KS accumulation is a hallmark of GCT, and that 5D4 and 297-11A could serve as diagnostic markers of GCT.